Exercise-Induced Shear Stress Modulates Metabolic Pathways for Vascular Repair and Protection Cardiovascular and metabolic diseases are on the rise in our veterans returning from battlefields in Afghanistan and the Middle East, and exercise intervention remains an effective lifestyle modification. Hemodynamic stress forces modulate both metabolic and mechanical effects on vascular endothelial cells, mediating the focal and eccentric nature of atherosclerotic lesions. The advent in metabolomics and metabolic profiling has led to the discovery of new metabolic biomarkers and therapeutic targets. We established that bidirectional oscillatory flow impairs autophagic flux, perturbing mitochondrial homeostasis. In contrast, unidirectional pulsatile flow attenuated mitochondrial DNA damage to maintain endothelial homeostasis. In parallel, we developed flexible micro-electrochemical impedance sensors for detection of metabolically active atherosclerotic lesions in the New Zealand White (NZW) rabbit model. We demonstrated that oxidized Low- Density Lipoprotein (oxLDL) in atherosclerotic lesions display distinct frequency-dependent electrical and dielectrical properties. Our preliminary studies revealed that pulsatile and oscillatory flow differentially modulated metabolic pathways to promote vascular regeneration and athero-protection. We demonstrated that flow-sensitive arterial metabolic changes were detected by electrochemical impedance spectroscopy (EIS). Furthermore, our metabolomics analyses revealed that PSS vs. OSS differentially activates PKC?-6- phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) signaling to increase glycolytic metabolites, but to decrease gluconeogenic metabolites, for vascular repair and regeneration. Metabolomics analyses further uncovered flow-sensitive nuclear hormone receptor peroxisome proliferator-activated receptor ? (PPAR?)-dependent fatty acid metabolites to mitigate monocyte recruitment. In this context, we hypothesize that exercise-augmented pulsatile shear stress (PSS) modulates glycolytic and lipid metabolic pathways to influence vascular regeneration and protection, leading to the arterial metabolic changes that can be detected by 3-D EIS mapping. To test our hypothesis, we have three aims. In Aim 1, we will determine if flow-mediated PKC? signaling modulates glycolytic metabolites for vascular regeneration. We hypothesize that PSS and OSS differentially modulate PKC?-PFKFB3 signaling pathway to regulate production of glycolytic metabolites. In Aim 2, we will determine if flow-sensitive PPAR? signaling modulates lipid metabolites for vascular protection. We hypothesize that PSS and OSS differentially modulate PPAR?-SCD-1 signaling to regulate production of fatty acid metabolites. In Aim 3, we will demonstrate shear stress-PPAR?- mediated arterial metabolic changes by 3-D EIS mapping. We hypothesize that PPAR?-SCD1-mediated metabolic changes can be interrogated by 3-D EIS mapping. Overall, the integration of vascular biology, hemodynamic forces and metabolomic profiling will provide metabolic insights into flow modulation of glycolytic and lipid metabolisms to discover new biomarkers with therapeutic implications for our veterans at risk for heart disease and metabolic syndromes.